SUMMARY Strabismus, a common binocular vision disorder that involves neuromuscular abnormality of the eyes, affects 18 million Americans. The disorder causes double vision, binocular confusion, eyestrain, and other symptoms that complicate daily activities. Strabismus is commonly treated surgically based on surgical intuition and tradition, but with reported disappointing success rates ranging from 30% to 80%. We propose to develop a novel data- driven modeling and simulation framework to simulate the neuro-biomechanics of strabismus that can bridge experimental studies and clinical application to advance our understanding and treatment of strabismus. We will develop the first three dimensional biomechanical model of the oculomotor system that incorporates recent findings on extraocular muscle pulleys and muscle compartments. Using clinical data from multiple individual cases as strong tests of the model, we will then develop generalized strategies for diagnosis and novel treatment for common but problematic classes (archetypes) of strabismus that require improved management. The knowledge gained from such systematic investigation can be directly applied clinically to assist future assessment and quantitative surgical dosing of similar patients without simulating every patient. The success of the proposed science-guided strabismus treatment approach could be utilized for other archetypes of strabismus as well as other oculomotor disorders to improve clinical outcomes. We will perform three sets of related analyses. In Aim 1, we will develop a novel computational model of the eyes capable of simulating binocular eye movement in three dimensions and overcoming limitations of existing models. For the first time, latest research findings on the functional compartmentalization of extraocular muscles and the actively-controlled pulley connective tissue gimbal system will be included in the biomechanical model. The developed model will be validated against empirical and clinical data so that it can be used rigorously in clinical simulation. In Aim 2 and Aim 3, we will leverage the model developed in Aim 1 to perform patient-specific strabismus simulation incorporating clinical data. The role of compartmentalization in the pathophysiology of two common types of cyclovertical strabismus, superior oblique palsy and sagging eye syndrome, will be examined. Different surgical interventions on treating these conditions will be simulated on patient-specific orbit models to assess the effectiveness of these surgical procedures. The outcome of this project will be a data-driven realistic neuro-biomechanical eye movement simulator, useful for scientific research, clinical insights, and evaluation of different types of surgical approaches to common forms of strabismus. Such a model can potentially improve our understanding of the functions of extraocular muscle compartmentalization in normal eye movements and in strabismus. It can also provide quantitative assessment of surgical intervention effectiveness and shed light on nonsurgical therapy of strabismus.